Tumor Necrosis Factor (TNF) is a pleiotropic cytokine, originally described for its ability to cause hemorrhagic necrosis of certain tumors in vivo (Carswell et al., 1975). In addition to its anti-tumor and anti-malignant cell effects, TNF has been reported to influence mitogenesis, differentiation and immunoregulation of various cell types.
The activities of TNF are mediated through two cell-surface receptors, namely TNF-R55 (CD120a) and TNF-R75 (CD120b), which are expressed by most cell types. TNF's effects are mediated primarily through TNF-R55. Upon activation of the receptor, adaptor proteins such as TRADD and TRAF are recruited and bind to the intracellular part of the clustered receptor (for review, see Wallach et al., 1999). These receptor-associated molecules that initiate signaling events are largely specific to the TNF/nerve growth factor receptor family. However, the downstream signaling molecules are not unique to the TNF system, but also mediate effects of other inducers. Downstream signaling molecules in the TNF system identified so far include: caspases, phospholipases, the three mitogen-activated protein (MAP) kinases, and the NF-κB activation cascade.
TNF-induced cell death in L929 cells is characterized by a necrosis-like phenotype and does not involve DNA fragmentation (reviewed by Fiers et al., 1999). It is independent of caspase activation and cytochrome c release, but is dependent on mitochondria and is accompanied by increased production of reactive oxygen intermediates (ROI) in the mitochondria that are essential to the death process (Goossens et al., 1995; Goossens et al., 1999). The latter was demonstrated by the fact that lipophylic anti-oxidantia, when added three hours after TNF treatment, could not only arrest the ongoing increased ROI production, but could also arrest cell death (Goossens et al., 1995). Furthermore, the mitochondria translocate from a dispersed distribution to a perinuclear cluster (De Vos et al., 2000); functional implications of this mitochondrial translocation remain unclear.
Glyoxalase I, together with glyoxalase II, constitutes the glyoxalase system that is an integral component of the cellular metabolism of α-ketoaldehydes and is responsible for the detoxification of the latter. The prime physiological substrate of the glyoxalase system is methylglyoxal (MG), which is cytotoxic. The major source of intracellular MG is the glycolysis namely, nonenzymatic and enzymatic elimination of phosphate from dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. The glyoxalase system, using glutathione (GSH) as cofactor, catalyzes the conversion of methylglyoxal to D-lactate in two consecutive steps. Glyoxalase I catalyzes the isomerization of the hemithioacetal, produced by the nonenzymatic conjugation of methylglyoxal with glutathione (GSH), to S-D-lactoylglutathione which is then hydrolyzed by glyoxalase II to D-lactate and GSH. D-lactate is then further metabolized to pyruvate by 2-hydroxy-acid dehydrogenase localized in the mitochondria. In addition to its role as a detoxification system, it has been suggested that glyoxalase I, together with its substrate MG, is involved in the regulation of cellular growth (for a review, see Kalapos, 1999), but until now this role has not been found. Increased expression of glyoxalase I occurs in diabetic patients and in some types of tumors such as colon carcinoma (Ranganathan et al., 1993), breast cancer (Rulli et al., 2001), prostate cancer (Davidson et al., 1999). It is also uniquely overexpressed in invasive human ovarian cancer compared to the low malignant potential form of this cancer (Jones et al., 2002). Also, hypoxia can lead to increased expression of glyoxalase I (Principato et al., 1990). Recently, it has been shown that glyoxalase I is involved in resistance of human leukemia cells to anti-tumor agent-induced apoptosis (Sakamoto et al., 2000).